To the Editor:
Traffic-related air pollution (TRAP) causes asthma morbidity, and vitamin D insufficiency (a plasma 25[OH]D level < 30 ng/ml) is associated with severe asthma exacerbations in Puerto Rican (PR) children (1). Because vitamin D has antioxidant effects, we examined whether proximity to a major road (a marker of TRAP) is associated with increased risk for severe asthma exacerbations in PR children and whether coexisting vitamin D insufficiency further increases this risk.
From March 2009 to June 2010, 351 children with asthma were chosen from randomly selected households in San Juan, Puerto Rico, as previously described (1). Study participants completed a protocol including questionnaires, spirometry, and allergy skin testing. Plasma 25-hydroxy-vitamin D (hereafter referred to as vitamin D) was measured using tandem mass spectrophotometry (Waters Corporation, Milford, MA) (1). Written parental consent and child’s assent was obtained for participants in the study, which was approved by the institutional review boards of the University of Puerto Rico in San Juan; Brigham and Women’s Hospital in Boston, Massachusetts; and the University of Pittsburgh in Pennsylvania.
To measure residential distance from a major road, the home address of each participant was geocoded (linked) to a 15-digit 2000 US Census Federal Information Processing Standard + block code at the University of Puerto Rico. Using the program ArcMAP10.1 (ArcGIS 10.1, Esri, Redlands, CA), centroids were then created by obtaining X, Y coordinates for the center of individual census blocks based on a 2000 US Census map for Puerto Rico (see Figure E1 in the online supplement). The distance from the residential block centroid of a participant to the nearest major road (defined by Esri 2012 Data and Maps major road layer) was then calculated using the geo-processing proximity tool “near,” which measures the nearest distance “as the crow flies” between two features. Because of the lack of a complete home address, one participant was excluded.
Our primary outcome was one or more severe asthma exacerbations (one or more hospitalizations or visits to the emergency department [ED] or urgent care requiring treatment with systemic corticosteroids, or one or more courses of systemic steroids [2]) in the previous year. Secondary outcomes included visits to the ED/urgent care and hospitalizations for asthma in the previous year.
Logistic multivariable regression was used for the analysis of TRAP and severe asthma exacerbations, adjusting for age, sex, household income, vitamin D insufficiency, and use of inhaled corticosteroids. To examine the joint effects of vitamin D insufficiency and proximity to a major road, we created four categories of exposure: vitamin D sufficiency and living furthest from a major road (in the upper or fourth quartile, based on results from a multivariate model), serving as the reference group; vitamin D sufficiency and living closer to a major road (first to third quartiles); vitamin D insufficiency and living furthest from a major road; and vitamin D insufficiency and living closer to a major road. Given nearly identical results for the two intermediate categories, they were collapsed, resulting in three categories for analysis: vitamin D sufficiency and living furthest from a major road, either living close to a major road or living farther from a road (but not both), and both living close to a major road and having vitamin D insufficiency.
Table E1 summarizes the characteristics of study participants: two-thirds or more lacked private/employer-based health insurance, nearly half were exposed to current or early-life environmental tobacco smoke (ETS), more than 40% had vitamin D insufficiency, slightly more than half had one or more severe exacerbations, and most were atopic. Proximity to a major road was significantly associated with one or more severe asthma exacerbations in the previous year.
Table E2 shows a comparison of children who either did or did not have one or more severe asthma exacerbations in the prior year by residential distance to a major road and other characteristics. Compared with children who had no severe exacerbations, those who did were significantly more likely to be younger and to have been exposed to ETS in early life, to have lower lung function and vitamin D insufficiency, and to not have used inhaled corticosteroids. There was also a trend for an inverse association between residential distance to a major road and one or more severe exacerbations (P = 0.05).
Table 1 shows the results of the multivariable analysis of residential distance to a major road and severe asthma exacerbations. Children living closer to a major road had two- to threefold increased odds of one or more severe exacerbation (Model 1). In this model, vitamin D insufficiency was also associated with 2.5 times increased odds of one or more severe exacerbations. Similar results were obtained when distance to a major road was treated as continuous (Model 2). Moreover, our findings were unchanged after additional adjustment for lung function measures or ETS in our multivariate models (data not shown).
Table 1.
Multivariate Analysis of Distance from a Major Roadway (by Quartiles [Model 1] and as a Continuous Variable [Model 2]) and Severe Asthma Exacerbations in Puerto Rican Children
| Covariates | Model 1 | Model 2 |
|---|---|---|
| Residential distance from a major roadway | By quartiles | Per every 100 m |
| Quartile 1 (<172 m) | 3.04* (1.43–6.45) | — |
| Quartile 2 (172–209 m) | 2.02* (1.01–4.06) | — |
| Quartile 3 (210–441 m) | 1.93 (0.94–3.99) | — |
| Quartile 4 (>441 m) | 1.00 (reference) | — |
| Continuous | — | 1.15*† (1.05–1.27) |
| Vitamin D insufficiency (plasma 25[OH]D level < 30 ng/dl) | 2.46* (1.43–4.28) | 2.46* (1.42–4.23) |
| Age, yr | 0.84* (0.75–0.93) | 0.87* (0.79–0.95) |
| Gender (male) | 1.19 (0.71–1.98) | 1.21 (0.73–2.01) |
| Annual household income > $15,000 | 0.81 (0.45–1.47) | 0.83 (0.48–1.45) |
| Inhaled corticosteroid use during the last 6 mo | 3.94* (2.16–7.19) | 3.97* (2.19–7.19) |
Data are given as odds ratio (95% confidence interval).
P < 0.01.
Per every 100 m closer to a major roadway, the odds of a severe exacerbation increase by ∼15%.
Figure 1 and Table E3 show the findings from an analysis stratified by categories of proximity to a road and vitamin D insufficiency. In this analysis, children who had either vitamin D insufficiency or lived closest to a major road were 1.6 times more likely to have had one or more severe asthma exacerbations than those who were vitamin D sufficient and lived furthest from a major road. Compared with children who were both vitamin D sufficient and lived furthest from a major road, those who were both vitamin D insufficient and lived closer to a major road were nearly five times more likely to have had one or more severe exacerbations. Findings for secondary outcomes were similar for ED/urgent care visits but less significant for hospitalizations for asthma, at least partly because of the small sample size (see Tables E4 and E5).
Figure 1.
Categories of residential proximity to a major roadway (living > vs. ≤441 m away from a major road) and vitamin D insufficiency (plasma vitamin D level < 30 ng/dl) and severe asthma exacerbations. Multivariate analysis adjusted for age, sex, household income, and use of inhaled corticosteroids in the prior 6 months.
Distance from a centroid may under- or overestimate residential distance from a major road, but this misclassification would be modest and nondifferential. Although we lack data on specific pollutants, examining TRAP by residential proximity to a major road integrates exposure to a complex milieu of pollutants (3), some of which (e.g., nitrogen dioxide, particulate matter and ozone) have been implicated in the pathogenesis of asthma and severe asthma exacerbations (4, 5). Seasonal variation has no major effect on vitamin D levels in Puerto Rico, and our findings were unchanged after accounting for month of sample collection or other relevant variables measured in our study. Confounding by unmeasured factors is a plausible but improbable explanation for our results, given prior findings implicating vitamin D insufficiency or TRAP as a risk factor for severe asthma exacerbations in children.
To our knowledge, this is the first report of joint detrimental effects of vitamin D insufficiency and TRAP on severe asthma exacerbations in children. Our findings suggest that airway oxidative stress induced by air pollutants is exacerbated by vitamin D insufficiency (6–8). Alternatively, vitamin D insufficiency and TRAP may impair immune responses to viral infections, a major cause of severe asthma exacerbations in childhood (9). Clinical trials should determine whether vitamin D ameliorates the negative effects of TRAP on asthma.
Footnotes
The authors are supported by grants HL079966 and HL117191 from the National Institutes of Health and by an endowment from the Heinz Foundation.
Author Contributions: G.C. and J.C.C. participated in study design and implementation; F.R., J.M.B., E.F., K.S.K., and J.C.C. participated in data analysis; E.A.-P. participated in data generation; F.R. and J.C.C. wrote the initial draft of the manuscript; and all authors participated in the review of the manuscript and approved its final version.
This letter has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Author disclosures are available with the text of this letter at www.atsjournals.org.
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